Recently available scientific evidence presented over the last decade strongly suggests that early exposure to commonly used general anesthetics during critical periods of brain development results in undue death of the immature nerve cells and long-term impairments in behavior (Jevtovic-Todorovic et al., 2003). In addition to very strong animal evidence, rapidly emerging human evidence points at the link between exposure to general anesthesia during critical periods of brain development and learning disabilities later in life (Wilder et al., 2009).
All currently approved general anesthetics that are commonly used in daily pediatric practice have been shown to be neurotoxic and detrimental to cognitive development. Since general exposure is often a necessity that cannot be avoided when child's health is in danger it is imperative that we consider the development of novel anesthetics that are safe and effective in providing amnesia, lack of consciousness and insensitivity to pain while lacking neurotoxic effects described with the use of current general anesthetics.
It appears that general anesthetics commonly used to achieve complete general anesthesia state are potent modulators of two key neurotransmitters—a major excitatory neurotransmitter, glutamate [via blocking N-methyl-D aspartate (NMDA) receptors], and a major inhibitory neurotransmitter, γ-amino-butyric acid (via potentiating GABAA receptors). Since glutamate and GABA regulate all aspects of early brain development it comes as no surprise that brain development is negatively impacted when general anesthesia is employed. This realization is posing an interesting challenge—could novel anesthetic drugs be developed with the mechanism of anesthetic action that do not directly implicate either GABA of glutamate but rather modulate different receptor system, and once developed, whether novel anesthetics with different anesthetic target would prove to be as effective as the existing anesthetics but safe for very young individuals?
T-type channels were first described in sensory neurons of the dorsal root ganglion and were shown to activate with small membrane depolarizations, thus making them an important regulator of nociceptive sensory neuron excitability (Nelson et al., 2005). Recent evidence suggests that modulation of peripheral T-channels influences somatic (e.g. thermal and mechanical) and visceral nociceptive inputs and that inhibition of T-currents results in significant anti-nociception in a variety of animal pain models (Todorovic and Jevtovic-Todorovic, 2013). Importantly, B260 (also referred to as 3β-OH) shows strong analgesic properties in vivo (Todorovic et al., 2004). In addition to having great analgesic potentials, modulation of T-channels in thalamic neurons in the brain is hypothesized to promote sedation and sleep depending on the degree of T channel inhibition. In addition, we have demonstrated recently that inhibition of R-type calcium channels in the thalamus is important for hypnotic effects of general anesthetics (Joksovic et al., 2009).
There is a long felt need in the art for anesthetics that are not neurotoxic. The present invention satisfies this need.